May 03, 2004

Interdisciplinary Triumph

Robert Freitas is the world's expert in nanomedicine, the use of advanced nanotechnology to build and run medical devices. He's writing a massive reference work on the topic.

Nanomedicine Volume I: Basic Capabilities discusses power, sensing, heat dissipation, control, navigation, and anatomy (with lots of numbers useful to engineers). And a lot of physics: Freitas bases his designs on the fundamental equations, and he shows his work. In fact, when I need to review the use of a physics formula, the first book I grab is Nanomedicine I. Then I try Nanosystems. My physics textbook usually stays on the shelf.

Nanomedicine IIA: Biocompatibility is an equally detailed book, with over 6,000 references. It goes into encyclopedic detail on immunology, cellular adhesion, and a wide variety of other topics. How can nanorobots hide from the immune system? Section 15.2.3.4. Will nanorobots make you throw up? Section 15.2.6.3. Are pure buckyballs biocompatible? Section 15.3.2.1. Will proteins stick to sapphire? Section 15.3.5.1. How elastic is the surface of an erythrocyte? Section 15.5.5.1.2.

(Why do all of these start with 15? Because in the original plan for a three-volume work on nanomedicine, chapter 15 was the biocompatibility chapter. But as Freitas did his research, the chapter grew...and grew...)

Comments

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The comprehensiveness of the scholarship in Nanomedicine is impressive, but I'm not always sure some of the judgements are fully backed up with evidence. One important example: I've always been a bit puzzled by the often-repeated claim that diamondoid surfaces are likely to be especially biocompatible or biologically inert. They are, after all (especially in the most likely hydrogen terminated case), pretty classic hydrocarbon-like hydrophobic surfaces, and proteins generally stick to hydrophobic surfaces like muck to a shovel.

There's very little literature on actual experimental results on protein adsorption on diamond (though there is some on the analogous hydrogen terminated silicon surface, including some from my group). What there is is correctly cited by Nanomedicine (primarily one study of fibrinogen adsorption) and this shows that this important protein does indeed quite substantially adsorb. So we have a single data point, but it is one that does not support the thesis. Nonetheless, the conclusion drawn is as follows:
"The hypothesis that atomically-precise diamond surfaces might possibly be engineered to be highly resistant to protein adsorption is suggested by the data but is not yet thoroughly substantiated".

This seems to me to be verging towards wishful thinking. Of course, the diamondoid surface studied was rough, but what evidence do we have that this makes any difference? Two recent studies give some pointers. Denis et al, in a paper "Protein adsorption on model surfaces with controlled nanotopography and chemistry" (Langmuir 18 819 (2002)) conclude... "the adsorbed amount is only affected by the surface chemistry", while the conclusion of another recent paper is in the title: "Nanometer-scale roughness having little effect on the amount or structure of adsorbed protein", Han et al, Langmuir 19 9868 (2003). And there is still the general issue - if proteins generally strongly adsorb to hydrophobic surfaces, including atomically flat ones, as abundant evidence shows, why should we think that diamondoid would be any different?

Going off on a tangent, it occurred to me that nanite medication could make our cells as effective at eliminating free radicals as those of a cockatiel are. Considering how long humans live now, how much longer could people be expected to live were that the case?

Alan, I don't think we are going to get a lot of mileage out of one simple change. But, when you understand how all the biomolecular processes work, and have the nano-machines to correct anything that goes wrong, you should be able to maintain the mechanism indefinitely.

Mike, protein would be very bad choice for a coating for diamondoid. The whole idea behind trying to make something biocompatible is to make it essentially invisible to the organism you put it in, and living organisms are very good at detecting proteins, whether foreign or home-made. An injection of protein coated nanobots into a human would almost certainly cause a serious allergic reaction. A better idea would be to use a grafted layer of polyethylene glycol, as used in stealth liposome technology, but the effect of even these layers doesn't last that long.

Yes, if you can't make the surface invisible, you ought to be able to make it look like something that the body takes for granted ought to be there. Which doesn't mean that the surface has to actually be made of this or that protien or lipid. The surface could be sculpted to look like a specific material.

I agree with many of the points made by Richard Jones in his first post. As he rightly notes, there is relatively little literature on actual experimental results on protein adsorption on diamond. More work is urgently needed. A central purpose for writing Nanomedicine Vol. IIA: Biocompatibility (NMIIA) (http://www.nanomedicine.com/NMIIA.htm) was not to provide final answers, but rather to begin asking the right questions and to point to further essential research that needs to be undertaken, in the context of medical nanorobot design, testing, and (eventually) clinical implementation.

Protein will indeed stick to diamond. On the other hand, diamond surfaces or diamond particles are commonly employed as the experimental null control material because diamond is so (relatively) biologically inert compared to other materials. The Tang study on fibrinogen adhesion used CVD diamond with poorly atomically-characterized surface topography and chemical functionalization. Accordingly, the description in NMIIA (http://www.nanomedicine.com/NMIIA/15.3.1.1.htm#p5) accurately concludes that "protein adhesion to near-atomically smooth diamond surfaces remains to be investigated." The introductory comment from NMIIA (http://www.nanomedicine.com/NMIIA/15.3.1.htm#p1) cited by Jones that "atomically-precise diamond surfaces might possibly be engineered to be highly resistant to protein adsorption" was not intended to exclude the engineering of surface chemical functionalization, the desired spatial ordering of which functionalization might be enhanced on an atomically precise, mechanically stiff diamond surface template.

For longer-term nanorobotic missions, or for semi-permanent implants, it seems likely that various classes of coatings (atop the diamondoid surface) may be useful in extending nanorobot biocompatibility in vivo. In another post, Jones validly suggests grafted PEG coatings, a very good idea discussed at length in NMIIA starting at http://www.nanomedicine.com/NMIIA/15.2.2.1.htm#p8. This pathway might well lead to success for short-duration medical nanorobot missions. Other approaches also seem promising, such as the artificial glycocalyx (http://www.nanomedicine.com/NMIIA/15.2.2.1.htm#p10), lipid-based techniques (http://www.nanomedicine.com/NMIIA/15.2.2.1.htm#p14) and stealth liposomes (http://www.nanomedicine.com/NMIIA/15.2.2.1.htm#p16) (one interesting experiment involved 75-nm Hb-functionalized diamond particles encapsulated inside liposomes; http://www.nanomedicine.com/NMIIA/Refs1400-1499.htm#1484), covalently-attached camouflaging proteins (http://www.nanomedicine.com/NMIIA/15.2.2.1.htm#p15, http://www.nanomedicine.com/NMIIA/15.2.3.3.htm#p23, http://www.nanomedicine.com/NMIIA/15.2.3.4.htm#p13, etc.), full encapsulation inside ghost-cell-derived membranes such as nanoerythrosomes http://www.nanomedicine.com/NMIIA/Refs5000-5099.htm#5049), immune evasion systems (http://www.nanomedicine.com/NMIIA/15.2.3.6.htm), and so forth. Chemical functionalization is clearly a major issue in biocompatible nanorobot design. That's why substantial portions of NMIIA Chapter 15.2 are devoted to this crucial topic.

I'd encourage everyone to examine NMIIA Chapter 15.2 (freely available online at http://www.nanomedicine.com/NMIIA/15.2.htm) and Section 15.3.1 on diamond biocompatibility (http://www.nanomedicine.com/NMIIA/15.3.1.htm), then consider initiating research aimed at investigating and improving biocompatibility on diamondoid surfaces. Biocompatibility is a complex and vital aspect of nanomedicine. Biocompatibility urgently deserves more research attention and more research funding.

It seems to me that soft surfaces - whether that's plain old PEG or something more sophisticated and biomimetic involving polysaccharides or lipids - is the way to go. My friends in the biomedical engineering world tell me that in-vivo PEG works much less well than you would hope based on in-vitro studies, but finding the proper choice of system involves a serach of a big parameter space that has hardly been explored. Clearly one wants to optimise the chemistry of the attachment points to get more robust layers, but also it isn't clear what combination of grafting density and chain length works best. Igal Szleifer at Purdue is doing some very nice theory based on the old notion that the non-adhesiveness of PEG brushes is essentially down to a steric stabilisation-like mechanism, which should be a good guide to experiments. We're just starting a set of experiments to characterise the nanoscale structure of PEG brushes, and hopefully in the future we'll extend this to explore the details of the interaction of PEG brushes with proteins.